title: The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster.
abstract: The coordination of cell proliferation and differentiation is crucial for proper development. In particular, robust mechanisms exist to ensure that cells permanently exit the cell cycle upon terminal differentiation, and these include restraining the activities of both the E2F/DP transcription factor and Cyclin/Cdk kinases. However, the full complement of mechanisms necessary to restrain E2F/DP and Cyclin/Cdk activities in differentiating cells are not known. Here, we have performed a genetic screen in Drosophila melanogaster, designed to identify genes required for cell cycle exit. This screen utilized a PCNA-miniwhite(+) reporter that is highly E2F-responsive and results in a darker red eye color when crossed into genetic backgrounds that delay cell cycle exit. Mutation of Hsp83, the Drosophila homolog of mammalian Hsp90, results in increased E2F-dependent transcription and ectopic cell proliferation in pupal tissues at a time when neighboring wild-type cells are postmitotic. Further, these Hsp83 mutant cells have increased Cyclin/Cdk activity and accumulate proteins normally targeted for proteolysis by the anaphase-promoting complex/cyclosome (APC/C), suggesting that APC/C function is inhibited. Indeed, reducing the gene dosage of an inhibitor of Cdh1/Fzr, an activating subunit of the APC/C that is required for timely cell cycle exit, can genetically suppress the Hsp83 cell cycle exit phenotype. Based on these data, we propose that Cdh1/Fzr is a client protein of Hsp83. Our results reveal that Hsp83 plays a heretofore unappreciated role in promoting APC/C function during cell cycle exit and suggest a mechanism by which Hsp90 inhibition could promote genomic instability and carcinogenesis.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; German Cancer Research Center (DKFZ) - Center for Molecular Biology Heidelberg (ZMBH) Alliance, Heidelberg, Germany.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bandura
authors.forename: Huaqi
authors.initials: H
authors.lastname: Jiang
authors.forename: Derek W
authors.initials: DW
authors.lastname: Nickerson
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Edgar
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000235:genetics; D000818:Animals; D064200:Cdh1 Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D014157:Transcription Factors; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics
chemical_list: D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; C496298:E2f1 protein, Drosophila; D006360:Heat-Shock Proteins; C089272:Hsp83 protein, Drosophila; D014157:Transcription Factors; C577674:fzr protein, Drosophila; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome